While much has been learned about the neurobiology of pain, it is disappointing that an insufficient number of novel therapies have been introduced into clinical practice. Moderate to severe pain is still treated mechanistically with opiate mu agonists and while some new mechanisms and improved formulations have improved patient care, it is widely acknowledged that the armamentarium available to physicians for the treatment of chronic pain is inadequate and that there is a large unmet medical need. The significance of our application is to address the clinical need for medications for injury or disease-induced chronic non-malignant pain with new mechanisms of action. Our goals in this PPG proposal are driven by the need of patients for new therapies to control pain as well as issues relevant to society including addiction and drug abuse. The proposals we have developed are comprehensive, multidisciplinary, and emphasize novel research hypotheses. This application brings together state-of-the-art chemistry, pharmacology, biophysics, biochemistry, and molecular biology all of which are necessary for success. Our central hypothesis is that drug design can consider known neural adaptations and mechanisms that may be relevant to specific pain conditions in order to develop improved pain therapeutics. We propose to design, synthesize and biologically validate multivalent drugs that can act as analgesics for the prolonged treatment of chronic non-malignant pain. The multifunctional characteristics of these single molecules are hypothesized to demonstrate diminished likelihood of drug addiction, drug seeking behavior, and tolerance without, or with greatly reduced, side effects that are present in currently available drugs and that diminish quality of life. Project A will be directed by Professo Victor Hruby and will focus on the discovery of multivalent opioid mu agonist-delta agonist and mu agonist/NK1 antagonist peptidic molecules with drug like characteristics and penetration across the blood brain barrier for delivery by systemic administration. Project B will be directed by Professors Frank Porreca and Ed Roberts and will aim to discover orally available and brain penetrant opioid mu/CCK antagonist molecules with drug like characteristics. Project C will be directed by Professors Alex Makriyannis, Todd Vanderah and Frank Porreca and will explore multifunctional cannabinoid agonists for improved treatment of HIV neuropathic pain. These projects will be supported by an Administrative Core (Hruby/Porreca), a synthetic core (Hruby) and a Biochemical Core (Vanderah/Streicher) that will allow maximal synergy and progress. Our goals are to discover single molecules with multiple receptor characteristics that have drug-like properties allowing for advancement to human trials for improved treatment of pain.